The outcome of Mycobacterium tuberculosis (Mtb) infection depends on host?s immune, metabolic and tissue- protective responses. Autophagy is a process that contributes to all three aspects of protection against tuberculosis (TB). The effectiveness or failure of autophagy and related processes is of direct relevance for central issues in TB. These include collusion between tuberculosis and HIV, immunometabolism and metabolic dysregulation in diabetes, tissue damage in the lung or other organs such as the central nervous system, and chronic pulmonary impairment or acute conditions following completion of chemotherapy. This project intends to define the role of autophagy and associated processes in active TB, TB latency, HIV- TB interactions, cellular metabolism, and as a cell/tissue-protective mechanism. Specifically, in this renewal application we will delineate how autophagy and related processes marshal metabolic and cytoprotective responses against Mtb in active and latent infection. While defining these relationships in the context of TB, we will uncover fundamental mechanisms of significance for diverse health and pathological states of both basic and translational value in TB. Based on our latest findings, we propose to focus on the endomembrane damage inflicted by Mtb in infected macrophages, as a trigger of cascading immunopathological and immunometabolic changes in the host. We refer to this set of cellular responses as membrane repair, removal and replacement (MERET). Autophagy is a key aspect of MERET, but MERET also includes immunometabolic switching, of relevance for tissue protection vs. pathogenesis, and for active TB disease vs. latency. The specific aims are: Aim 1 Define the in vivo role of key autophagy factors in protection against Mtb. This aim will focus on the role of the sole integral membrane autophagy (ATG) factor, ATG9, as the ultimate test of the role of autophagic membranes in protection against active or latent TB. We will use murine models of acute and chronic Mtb infection to test whether autophagy prevents or favors transitions to latent infection. Aim 2. Determine the roles of TBK1 and ATG9 during critical stages of autophagy. We will focus on ATG9 and TBK1 and how these factors contribute to cytoplasmic homeostasis and protection against Mtb. Points of HIV interference will be tested. Aim 3, Define host cell responses to endomembrane damage associated with Mtb infection. We will focus on endomembrane damage, an intriguing but poorly understood phenomenon occurring during Mtb infection of macrophages. We will test the hypothesis that host cell membrane damage caused by Mtb is a critical determinant of autophagic and immunometabolic control of TB.